The present invention relates to novel intermediates, processes for the preparation thereof and processes for the preparation of optically active octanoic acid derivatives by using intermediates.
More particularly, the present invention relates to novel intermediates, i.e., N-(2S-(2-propenyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam, N-(2S-(2-propynyl) octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam and N-(2R-(2-propyl) octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam; processes for the preparation thereof; and processes for the preparation of optically active 2S-(2-propenyl)octanoic acid, 2S-(2-propynyl)octanoic acid and 2R-propyloctanoic acid by using thereof intermediates.
The optically active octanoic acid derivatives prepared by the present invention are intermediates useful for the preparation of medicaments or are compounds useful as medicaments. For example, a racemate of 2R-propyloctanoic acid is described in Example 7(33) of JP-A-7-316092 as an agent for treating or preventing neurodegenerative diseases derived from functional abnormality of astrocytes.
As a result of the study after that, it was found that optically active 2R-propyloctanoic acid has strong activities in particular. Accordingly, methods for obtaining this compound efficiently have been studied variously, and the following processes are known until now.
For example, JP-A-8-291106 discloses a method by optical resolution using optically active amine. However, in the process of optically separating 2R-propyloctanoic acid from its racemate, both the chemical yield (total synthetic yield of 5.9% at 6 stages from dimethyl hexylmalonate) and the optically purity (90.0% e.e.) were so insufficient that the process had no practical use.
A process using an optically active starting material is known as other process for obtaining optically active 2R-propyloctanoic acid. For example, JP-A-8-295648 discloses a process using optically active prolinol. An optically active branched alkanoic acid having a high optical purity (96.0% e.e.) can be prepared using this process. However, the chemical yield (total synthetic yield of 20.1% at 5 stages from pentanoyl chloride) was so insufficient that the process did not necessarily have a practical use.
The present inventor has found that novel intermediates, i.e., N-(2S-(2-propenyl) octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam, N-(2S-(2-propynyl) octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam and N-(2R-(2-propyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam, by using optically active (1S)-(xe2x88x92)-2,10-camphorsultam, further processes for the preparation of optically active 2S-(2-propenyl)octanoic acid, 2S-(2-propynyl)octanoic acid and 2R-propyloctanoic acid as high optical purity (95-99% e.e.) by using thereof intermediates, accomplished the present invention.
That is, the present invention relates to novel intermediates, processes for the preparation thereof and processes for the preparation of optically active octanoic acid derivatives by using intermediates as follows:
[1] A compound of N-(2S-(2-propenyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam, N-(2S-(2-propynyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam, or N-(2R-(2-propyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam;
[2] A compound of N-(2S-(2-propenyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam depicted in [1];
[3] A compound of N-(2S-(2-propynyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam depicted in [1];
[4] A compound of N-(2R-(2-propyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam depicted in [1];
[5] A process for the preparation of N-(2S-(2-propenyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam depicted in [2], which is characterized by the reaction of N-octanoyl-(1S)-(xe2x88x92)-2,10-camphorsultam with allyl halide;
[6] A process for the preparation of N-(2S-(2-propynyl) octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam depicted in [3], which is characterized by the reaction of N-octanoyl-(1S)-(xe2x88x92)-2,10-camphorsultam with propargyl halide;
[7] A process for the preparation of N-(2R-(2-propyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam depicted in [4], which is characterized by the reduction of N-(2S-(2-propenyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam depicted in [2];
[8] A process for the preparation of N-(2R-(2-propyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam depicted in [4], which is characterized by the reduction of N-(2S-(2-propynyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam depicted in [3];
[9] A process for the preparation of optically active 2S-(2-propenyl)octanoic acid, which is characterized by the hydrolysis of N-(2S-(2-propenyl) octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam depicted in [2];
[10] A process for the preparation of optically active 2R-propyloctanoic acid, which is characterized by the reduction of optically active 2S-(2-propenyl) octanoic acid obtained in [9];
[11] A process for the preparation of optically active 2S-(2-propynyl)octanoic acid, which is characterized by the hydrolysis of optically active N-(2S-(2-propynyl) octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam depicted in [3]
[12] A process for the preparation of optically active 2R-propyloctanoic acid, which is characterized by the reduction of optically active 2S-(2-propynyl) octanoic acid obtained in [11].
[13] A process for the preparation of optically active 2R-propyloctanoic acid, which is characterized by the hydrolysis of optically active N-(2R-(2-propyl) octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam depicted in [4].
Optically active 2R-propyloctanoic acid in high optical purity (95-99% e.e.) and superior chemical yield (4 steps from octanoyl chloride, total synthetic yield 42.5-72.1%) can be efficiently prepared by the method of the present invention. Further the hydrolysis of camphorsultam derivatives by using tetraalkylammonium hydroxide is novel reaction. This observation has been confirmed from experiments by the present inventor for the first time.
Novel intermediate compounds of the present invention can easily improve optical purity by recrystallization since novel intermediates compounds are easily crystallized. For example, the residue of the reaction was purified by column chromatography to give N-(2S-(2-propynyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam having 96.8% diastereoisomer excess (liquid chromatography). Further thus obtained compound could be improved to give it having 99.4% diastereoisomer excess (liquid chromatography) by recrystallization.
In the present invention, the process for the preparation of 2R-propyloctanoic acid may be carried out four methods (A) to (D) as follows, respectively.
(A) 2R-propyloctanoic acid may be prepared by reacting of camphorsultam with octanoic acid or its derivativesxe2x86x92the reaction of allyl halidexe2x86x92hydrolysisxe2x86x92reduction;
1) reacting of (1S)-(xe2x88x92)-2,10-camphorsultam with octanoic acid or its derivatives,
2) reacting of N-octanoyl-(1S)-(xe2x88x92)-2,10-camphorsultam with ally halide,
3) hydrolysis of N-(2S-(2-propenyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam, and
4) reduction of optically active 2S-(2-propenyl)octanoic acid.
(B) 2R-propyloctanoic acid may be prepared by reacting of camphorsultam with octanoic acid or its derivativesxe2x86x92the reaction of propargyl halidexe2x86x92hydrolysisxe2x86x92reduction;
1) reacting of (1S)-(xe2x88x92)-2,10-camphorsultam with octanoic acid or its derivatives,
2) reacting of N-octanoyl-(1S)-(xe2x88x92)-2,10-camphorsultam with propargyl halide,
3) hydrolysis of N-(2S-(2-propynyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam, and
4) reduction of optically active 2S-(2-propynyl)octanoic acid.
(C) 2R-propyloctanoic acid may be prepared by reacting of camphorsultam with octanoic acid or its derivativesxe2x86x92the reaction of allyl halidexe2x86x92reductionxe2x86x92hydrolysis;
1) reacting of (1S)-(xe2x88x92)-2,10-camphorsultam with octanoic acid or its derivatives,
2) reacting of N-octanoyl-(1S)-(xe2x88x92)-2,10-camphorsultam with ally halide,
3) reduction of N-(2S-(2-propenyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam, and
4) hydrolysis of N-(2S-(2-propyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam.
(D) 2R-propyloctanoic acid may be prepared by reacting of camphorsultam with octanoic acid or its derivativesxe2x86x92the reaction of propargyl halidexe2x86x92reductionxe2x86x92hydrolysis;
1) reacting of (1S)-(xe2x88x92)-2,10-camphorsultam with octanoic acid or its derivatives,
2) reacting of N-octanoyl-(1S)-(xe2x88x92)-2,10-camphorsultam with propargyl halide,
3) reduction of N-(2S-(2-propynyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam, and
4) hydrolysis of N-(2S-(2-propyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam.
The summary of the above four methods was shown in Scheme 1.
In the Scheme 1;
X represent elimination group generally known (e.g., p-toluenesulfonyl, methanesulfonyl, chloride, bromide or iodide atom etc.). 
The reaction of (1S)-(xe2x88x92)-2,10-camphorsultam with octanoic acid or its derivatives is known per se (Tetrahedron, 48, 2453 (1992)), and may be carried out by, for example, using an acid halide.
The method using an acid halide may be carried out, for example, by reacting a octanoic acid with an acid halide (e.g., oxalyl chloride, thionyl chloride etc.) in an inert organic solvent (e.g., chloroform, dichloromethane, diethyl ether, tetrahydrofuran etc.) or without a solvent at from xe2x88x9220xc2x0 C. to the reflux temperature of the solvent, and then by reacting octanoyl chloride obtained with (1S)-(xe2x88x92)-2,10-camphorsultam in the presence of an base [tertiary amine (e.g., pyridine, triethylamine, dimethylaniline, dimethylaminopyridine etc.), hydroxide of an alkali metal (e.g., sodium hydroxide, potassium hydroxide, etc.) or organic lithium (e.g., n-butyllithium, phenyllithium etc.)] in an inert organic solvent (e.g., chloroform, dichloromethane, diethyl ether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, toluene etc.), at a temperature of from 0xc2x0 C. to 40xc2x0 C.,
This reaction preferably may be carried out in an atmosphere of inert gas (e.g., argon, nitrogen etc.) under anhydrous conditions.
The alkylation of N-octanoyl-(1S)-(xe2x88x92)-2,10-camphorsultam with alkyl halide or propagyl halide may be carried out by using organic metal. The alkylation by using organic metal is known per se, and may be carried out, for example, by reacting N-octanoyl-(1S)-(xe2x88x92)-2,10-camphorsultam with allyl halide or propargyl halide in the presence or absence of an iodide of an alkali metal (e.g., lithium iodide, sodium iodide, potassium iodide, etc.) and in the presence of an base (e.g., n-butyllithium, sec-butyllithium, t-butyllithium, phenyllithium, diisoporopyllithium, potassium hydroxide, sodium hydroxide, etc.) in an inert organic solvent (e.g., tetrahydrofuran, dioxane, diethyl ether, benzene, dimethoxyehtane, hexane, cyclohexane, hexamehtlphosphoramide, dimethylindazolidione or a mixture of them, etc.), at a temperature of from xe2x88x9270xc2x0 C. to 20xc2x0 C.
The reduction of optically active 2S-(2-propenyl)octanoic acid, optically active 2S-(propynyl)octanoic acid, N-(2S-(2-propenyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam or N-(2S-(2-propynyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam may be carried out by using catalytic reduction.
The catalytic reduction is known per se, and may be carried out, for example, in an inert solvent (e.g., ethyl acetate tetrahydrofuran, tetrahydropyran, dioxane, diethoxyethane, diethyl ether, biphenyl ether, methanol, ethanol isopropanol, benzene, toluene, xylene, acetone, methyl ethyl ketone, phenyl methyl ketone, acetonitrile, hexamethylphosphoramide, dimethylformamide dimethylimizazolidine, mixture of them etc.), by using a catalyst (e.g., palladium on carbon, palladium, platinum, platinum oxide, nickel, palladium hydroxide on carbon, rhodium, rhodium on carbon, ruthenium, ruthenium on carbon, tris(triphenylphosphine)chlororhodium, etc.) under an atmosphere of hydrogen, at a temperature of from 0xc2x0 C. to 60xc2x0 C.
The hydrolysis of N-(2S-(2-propenyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam, N-(2S-(2-propynyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam or N-(2S-(2-propyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam may be carried out by methods as follows.
(i) The hydrolysis by using hydroxide of an alkali metal is known per se (Tetrahedron, 43, 1969 (1987) or Helv. Chim. Acta., 72, 1337 (1989)), and may be carried out, for example, in the presence or absence of a peroxide (e.g., hydroperoxide, t-butylhydroperoxide an aqueous solution them, etc.), by using hydroxide of an alkali metal (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, an aqueous solution them, etc.) in a water-miscible solvent (tetrahydrofuran, dioxane, a mixture of water and them, etc.) at a temperature of from 0xc2x0 C. to 40xc2x0 C.
It is known that this reaction was proceeded without racemization and the obtained compound was given to maintain optical purity.
(ii) The hydrolysis by using tetraalkylammonium hydroxide is quite novel reaction.
This reaction may be carried out, for example, in the presence or absence of a peroxide (e.g., hydroperoxide, t-butylhydroperoxide an aqueous solution them, etc.) by using tetraalkylammonium hydroxide (e.g., tetrabutylammonium hydroxide, tetraoctylammonium hydroxide, tetradecylammonium hydroxide, an aqueous solution them, etc.) in a water-miscible solvent (tetrahydrofuran, dimethoxyethane, t-butanol, dioxane, a mixture of water and them, etc.) at a temperature of from xe2x88x9220xc2x0 C. to 40xc2x0 C. With the proviso that, when camphorsultam derivatives have double or triple bond, this reaction may be carried out in the presence of an excess amount of the compound having double bond (e.g., 2-methyl-2-butene, etc.) since the protection of the compound having double or triple bond is oxidized by peroxide.
It is known that this reaction was proceeded without racemization and the obtained compound was given to maintain optical purity.
Furthermore, optically active 2R-(2-propenyl)octanoic acid, 2R-(2-propynyl) octanoic acid or 2S-propyloctanoic acid may be prepared by the same procedure as the method of the present invention using (1R)-(+)-2,10-camphorsultam instead of (1S)-(xe2x88x92)-2,10-camphorsultam.
N-(2S-(2-propenyl)octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam, N-(2S-(2-propynyl) octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam and N-(2R-(2-propyl) octanoyl)-(1S)-(xe2x88x92)-2,10-camphorsultam in the present invention are not described in the literature, therefore they are novel compound. They are useful as intermediate of process for the preparation of 2R-propyloctanoic acid.
The racemate of 2S-(2-propenyl)octanoic acid as intermediate of the present invention is known per se, in the literature of Chem. Pharm. Bull., 24, 538 (1976). The racemate of 2S-(2-propynyl)octanoic acid is known per se, in the literature of Tetrahedron Lett., 25, 5323 (1984). (1S)-(xe2x88x92)-2,10-camphorsultam is known per se, as the CAS registry No. 94594-90-8. N-octanoyl-(1S)-(xe2x88x92)-2,10-camphorsultam is known per se, in the literature of Tetrahedron, 48, 2453 (1992). 2S-(2-propynyl)octanoic acid is known per se, in JP-A-8-291106.